[Analysis of the efficacy and safety of bone disease treatment in patients with newly diagnosed multiple myeloma treated with denosumab or zoledronic acid].

Objective: This study investigated the efficacy and safety of denosumab (DENOS) versus zoledronic acid (ZOL) in the bone disease treatment of newly diagnosed multiple myeloma. Methods: The clinical data of 80 patients with myeloma bone disease (MBD) at the Fifth Medical Center of PLA General Hospital between March 1, 2021 and June 30, 2023 were retrospectively reviewed. Eighteen patients with severe renal impairment (SRI, endogenous creatinine clearance rate<30 ml/min) were treated with DENOS, and 62 non-SRI patients were divided into DENOS (30 patients) and ZOL group (32 patients) . Results: Hypocalcemia was observed in 26 (33%) patients, and 22 patients developed hypocalcemia during the first treatment course. The incidence of hypocalcemia in the non-SRI patients of DENOS group was higher than that in the ZOL group [20% (6/30) vs 13% (4/32), P=0.028]. The incidence of hypocalcemia in SRI was 89% (16/18). Multivariate logistic regression analysis revealed that endogenous creatinine clearance rate<30 ml/min was significantly associated with hypocalcemia after DENOS administration (P<0.001). After 1 month of antiresorptive (AR) drug application, the decrease in the serum ß-C-terminal cross-linked carboxy-telopeptide of collagen type I concentrations of SRI and non-SRI patients in the DENOS group were significantly higher than that in the ZOL group (68% vs 59% vs 27%, P<0.001). The increase in serum procollagen type Ⅰ N-terminal propeptide concentrations of patients with or without SRI in the DENOS group were significantly higher than that in the ZOL group (34% vs 20% vs 11%, P<0.05). The level of intact parathyroid hormone in each group increased after AR drug treatment. None of the patients developed osteonecrosis of the jaw and renal adverse events, and no statistically significant differences in the overall response rate, complete remission and stringent complete remission rates were found among the groups (P>0.05), and the median PFS and OS time were not reached (P>0.05) . Conclusions: In the treatment of MBD, DENOS minimizes nephrotoxicity and has strong AR effect. Hypocalcemia is a common adverse event but is usually mild or moderate and manageable.

Claudin-10 Decrease in the Submandibular Gland Contributes to Xerostomia.

Tight junction proteins play a crucial role in paracellular transport in salivary gland epithelia. It is clear that severe xerostomia in patients with HELIX syndrome is caused by mutations in the claudin-10 gene. However, little is known about the expression pattern and role of claudin-10 in saliva secretion in physical and disease conditions. In the present study, we found that only claudin-10b transcript was expressed in human and mouse submandibular gland (SMG) tissues, and claudin-10 protein was dominantly distributed at the apicolateral membranes of acini in human, rat, and mouse SMGs. Overexpression of claudin-10 significantly reduced transepithelial electrical resistance and increased paracellular transport of dextran and Na+ in SMG-C6 cells. In C57BL/6 mice, pilocarpine stimulation promoted secretion and cation concentration in saliva in a dose-dependent increase. Assembly of claudin-10 to the most apicolateral portions in acini of SMGs was observed in the lower pilocarpine (1 mg/kg)-treated group, and this phenomenon was much obvious in the higher pilocarpine (10 mg/kg)-treated group. Furthermore, 7-, 14-, and 21-wk-old nonobese diabetic (NOD) and BALB/c mice were used to mimic the progression of hyposalivation in Sjögren syndrome. Intensity of claudin-10 protein was obviously lower in SMGs of 14- and 21-wk-old NOD mice compared with that of age-matched BALB/c mice. In the cultured mouse SMG tissues, interferon-γ (IFN-γ) downregulated claudin-10 expression. In claudin-10-overexpressed SMG-C6 cells, paracellular permeability was decreased. Furthermore, IFN-γ stimulation increased p-STAT1 level, whereas pretreatment with JAK/STAT1 antagonist significantly alleviated the IFN-γ-induced claudin-10 downregulation. These results indicate that claudin-10 functions as a pore-forming component in acinar epithelia of SMGs, assembly of claudin-10 is required for saliva secretion, and downregulation of claudin-10 induces hyposecretion. These findings may provide new clues to novel therapeutic targets on hyposalivation.

[Daratumumab maintenance after autologous hematopoietic stem cell transplantation for newly diagnosed multiple myeloma].

Objective: This study aimed to evaluate the efficacy and safety of daratumumab as a maintenance treatment after autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with newly diagnosed multiple myeloma (NDMM) . Methods: The clinical data, hematological and renal response, and safety of 15 post-transplant patients with NDMM who had received daratumumab maintenance between May 1, 2022 and June 30, 2023 were retrospectively analyzed. Results: Fifteen patients (11 males and 4 females) with a median age of 58 (41-72) years were included. Thirteen patients did not receive daratumumab during induction therapy and auto-HSCT, 6 patients had renal impairment, and nine patients had high-risk cytogenetics. The median infusion of daratumumab was 12 (6-17) times, and the median duration of maintenance was 6 (1.5-12) months. The treatment efficacy was evaluated in all 15 patients, and daratumumab maintenance therapy increased the rate of stringent complete response from 40% to 60%. The renal response rate and median estimated glomerular filtration rate of six patients with RI-NDMM were also improved. During daratumumab maintenance therapy, the most common hematological grade 3 adverse event (AE) was lymphopenia [4 of 15 patients (26.67%) ], whereas the most common nonhematologic AEs were infusion-related reactions [7 of 15 patients (46.67%) ] and grade 3 pneumonia [5 of 15 patients (33.33%) ]. The five patients with pneumonia were daratumumab naive [5 of 13 patients (38.46%) ], with a median of 8 (6-10) infusions. Among them, the chest computed tomography of three patients showed interstitial infiltrates, and treatment with methylprednisolone was effective. With a median follow-up of 12 months, the 1-year overall survival rate was 93.33%, and only one patient died (which was not related to daratumumab treatment) . Conclusions: Daratumumab was safe and effective as a maintenance agent for post-auto-HSCT patients with NDMM, and AEs were controllable. The most common nonhematologic AE was grade 3 pneumonia, and a less dose-intense maintenance regimen for the first 8 weeks could reduce the incidence of pneumonia.

Hypoxic-ischaemic brain damage in immature rats: effects of adrenoceptor modulation.

The purpose of the present study was to evaluate the role of adrenergic receptors in the cascade leading to hypoxic-ischaemic brain injury in neonatal rats. The effect of adrenergic agents (prazosin, yohimbine, idazoxan and clonidine) administered before or after hypoxia-ischaemia was evaluated with respect to mortality and brain injury. Rat pups of either 7 or 8 days of age were subjected to unilateral carotid artery ligation combined with hypoxia (6% or 8% O2 in N2). The mortality was higher in hypoxic-ischaemic groups pre-treated with the alpha-adrenergic receptor antagonists prazosin (48%) or yohimbine (53%) than in saline controls (7%). After 2 weeks the severity of the brain injury was evaluated in the surviving rats. Unilateral brain injury, evaluated by brain weight deficit of the injured ipsilateral hemisphere compared with the contralateral hemisphere, was 17.8 +/- 4.9% and 27.1 +/- 4.0% in pre- and post-treated saline groups, respectively. Post-treatment with clonidine, an alpha2-adrenergic agonist, reduced brain injury by 45% (p < 0.05) compared with saline controls. Pre-treatment with the same drug was not effective. Idazoxan had no effect on brain injury in this animal model. The results indicate that activation of central alpha2-adrenergic or imidazole receptors provides neuroprotection during reperfusion after hypoxic-ischaemic brain injury in neonatal rats.

Apoptosis induced by 5-flucytosine in human pancreatic cancer cells genetically modified to express cytosine deaminase.

AIM: To elucidate the pattern of 5-flucytosine (5-FC)-induced apoptosis and its role in gene therapy of human pancreatic cancer. METHODS: The human pancreatic cancer SW1990 cells (CEA-producing) were infected with recombinant adenoviruses (Adex1CEA-prCD or Adex1CEA-prZ). Expression of CD gene protein was examined by western blot. Apoptosis induced by 5-FC in human pancreatic cancer SW1990 cells genetically modified to express cytosine deaminase was observed by means of electron microscopy, DNA electrophoresis, and flow cytometry analysis techniques. RESULTS: The SW1990 cells infected with Adex1CEA-prCD were treated with 5-FC at 100 mumol.L-1 for 48 h, and cell apoptosis was observed. Typical apoptosis morphological feature appeared and DNA ladder could be demonstrated on DNA electrophoresis. Apoptosis peak was also showed by flow cytometry. Apoptotic cells accounted for 34.6% of the cell population. Cells in G1, S, and G2/M phase of cell cycle were 64%, 11%, and 7%, respectively. CONCLUSION: The apoptosis induced by 5-FC may be a primary mechanism in CD gene therapy of pancreatic cancer.

Differential north to south gastric cancer-duodenal ulcer gradient in China. China Ulcer Study Group.

There are suggestions that duodenal ulcer protects individuals from gastric cancer and that rice is ulcerogenic while wheat is gastro-protective. We aimed to examine the relationship of gastric cancer, duodenal and gastric ulcers in different geographical regions in China and identified dietary risk factors for duodenal ulcer and gastric cancer. The prevalence of peptic ulcer and gastric cancer among symptomatic patients in eight major cities, four each from the north and the south representing all the six defined regions of China were studied. Endoscopy and case records over a 10 year period were reviewed and cases of confirmed duodenal and gastric ulcer and gastric cancer, together with the total number of endoscopies performed per year, were recorded. Rates were expressed as cases/1000 endoscopies. Results were compared to another epidemiological study on diet and mortality in the same regions in China conducted at the same time. Duodenal ulcer rates were 2.4-fold higher in southern China than northern China, whereas gastric cancer rates were 1.6-fold higher in the north than in the south. Correlation studies showed for the first time an inverse linear relationship between the gastric cancer rates and the duodenal ulcer rates (r=-0.8076, P=0.015), as well as the duodenal ulcer: gastric ulcer ratios (r=-0.9133, P=0.002). Gastric ulcer rates were higher in southern China but did not correlate with the gastric cancer rates (r=0.1455, P=0.731). Duodenal ulcer rates were found to be related to daily rice intake (r=0.8554, P=0.029) and inversely related to daily wheat flour intake (r=-0.8472, P=0.033). Gastric cancer rates were not related to any dietary risk factors tested. We concluded there was an inverse relationship between gastric cancer rates and duodenal ulcer rates. Although duodenal ulceration and gastric cancer are both linked to Helicobacter pylori infection, the findings of this study indicate independent additional aetiological factors for the pathogenesis of these conditions. Dietary factors such as rice or wheat intake may play a role.

Adrenalectomy reduces the ability of newborn rats to gasp and survive anoxia.

The ventilatory response to anoxia in unanaesthetized rat pups of 1 and 8 days of age was studied. Ventilation was recorded by barometric plethysmography. During acute anoxia (100% N2), animals of both ages responded with hyperpnoea, primary apnoea, hypoxic gasping and secondary apnoea. After secondary gasping, occasional gasps occurred. If oxygen was administered during the gasping period, all animals survived through autoresuscitation. The duration of the period of hypoxic gasping was significantly longer in the 1-day-old animals. Adrenalectomy reduced the length of this period in both 1- and 8-day-old animals. In a second series of experiments, the effect of adrenergic antagonists on autoresuscitation was examined. Pretreatment with the non-selective alpha-receptor antagonist phentolamine reduced the duration of gasping in 1-day-old rats, but prolonged this duration in 8-day-old rats. The non-selective beta-receptor antagonist propranolol did not affect the duration of gasping in 1-day-old rats, whereas it prolonged this period in the older animals. We conclude that proper duration of gasping during anoxia is dependent on intact adrenal function and that the adrenal glands therefore play an important role in autoresuscitation from anoxia during postnatal life. The underlying mechanism appears to involve alpha-adrenergic receptors.

Effects of hyperglycemia on gasping and autoresuscitation in newborn rats.

The aim of this study was to test the effects of glucose on the gasping ability and survival in a rat pup model during acute anoxia. Newborn rat pups of both 1 and 8 days of age were given glucose (30 and 60 mg/animal) or saline intraperitoneally and subsequently subjected to anoxia (100% N2). Glucose supplement induced hyperglycemia. Respiration was recorded by barometric plethysmography. The rat pups responded to acute anoxia with a robust sequence of respiratory pattern: hyperpnea, primary apnea, hypoxic gasping and secondary apnea. During anoxia the 1-day-old rats gasped much longer than the 8-day-old rats (23.4 +/- 1.0 vs. 6.1 +/- 0.5 min, p < 0.001). No difference was found in gasping duration between the saline control and the glucose-supplemented 1-day-old rat pups. The 8-day-old supplemented rats gasped much longer (9.3 +/- 0.5 min) than the control rats (6.1 +/- 0.5 min, p < 0.01). The animals autoresuscitated when they received oxygen (100%) during the gasping period. When oxygen was given after the gasping period, the survival rate was 33.3% in control and 0% in supplemented 1-day-old rats, and 100% in control and 50% in glucose-supplemented 8-day-old rats (p < 0.02). Further controlled experiments for a fixed period of anoxia to 13.5 min resulted in survival rates of 50.0% for controls and 28.6% for supplemented animals, respectively. The overall survival rate was then 85.2% in control and 52.9% in supplemented 8-day-old rats (p < 0.05). Lactate concentration in blood rapidly increased in the first 6 min of anoxia and thereafter gradually increased to 22.1 mmol/l around the last gasp in the 1-day-old rats. Hyperglycemia did not cause further accumulation of lactate despite a transient elevation over the control rats at 6 min of anoxia. In the 8-day-old supplemented animals the lactate level was only modestly increased, probably due to the prolonged gasping period. In conclusion, we found that gasping performance was well preserved in the 8-day-old glucose-supplemented rats, whereas the autoresuscitation mechanism after the last gasp might be altered due to hyperglycemia. In addition, the accumulation of lactate in the blood did not affect the gasping performance and the mechanisms of autoresuscitation.

Cerebral and ventilatory depression during hypoxia in anaesthetized newborn guinea-pigs.

The effects of hypoxia on ventilation and cerebral activity were studied in urethane-anaesthetized newborn guinea-pigs. Ventilation was measured by a pneumotachograph, and cerebral activity by a cerebral function monitor (CFM). All animals were subjected to either 9% O2 or 6% O2 in N2 for 10 minutes or until apnoea occurred. Hypoxia produced a biphasic response in ventilation, that is, an increase followed by a decrease. The initial increase was attributed to the elevation of the respiratory rate, whereas the tidal volume showed a pure decline. The respiratory rate reached its peak at 3 minutes of hypoxia (170 +/- 12% during 9% O2 and 169 +/- 12% during 6% O2). Cerebral activity during both 9 and 6% O2 breathing showed a small increase followed by a decrease. In the group subjected to 9% O2 the maximum CFM activity increased to 114 +/- 8% of the control level and the minimum activity increased to 113 +/- 7%, while in the group subjected to 6% O2 the maximum CFM activity increased to 104 +/- 5% and the minimum CFM activity to 101 +/- 3%. The depression of CFM activity was more pronounced with 6% O2 than with 9% O2. Regression analysis showed a linear correlation between ventilation and cerebral activity during both 9 and 6% O2 breathing. The results suggest that hypoxic ventilatory depression may be the consequence of cerebral depression produced by acute severe hypoxia.

[The anti-pancreatic cancer efficacy of LAK cells mediated by YPC3 monoclonal antibody in vitro and in vivo].

The purpose of this study was to investigate a new form of specific targeting immunotherapy for human pancreatic carcinoma. In 4hr 51Cr release assays, the cytolysis of Capan-2 human pancreatic carcinoma cells by LAK cells was enhanced with pancreatic cancer-specific monoclonal antibody (YPC3 McAb). This antibody-dependent cellular cytotoxicity (ADCC) of the LAK cells was more evident while increasing the concentration of YPC3 McAb. The cytotoxic effects of the LAK cells on target cells increased about 60% when 50 micrograms/ml of YPC3 McAb was used. No cytotoxic effect of the LAK cells was found in the presence of irrelevant monoclonal antibody. Experimentally, the growth rate of Capan-2 human pancreatic carcinoma cell line in nude mice was 25%, 100%, and 100% after the injection of LAK cells, splenocytes and YPC3 McAb, respectively. However, simultaneous injection of YPC3 McAb and LAK cells completely inhibited the growth of the cell line. These results suggest that LAK cells in combination with YPC3 McAb might be useful for the treatment of human pancreatic carcinoma.

Investigation on lymphocyte subpopulations in the intestinal lamina propria in inflammatory bowel diseases.

Intestinal lamina proprial lymphocytes were enumerated in 13 patients with Crohn's disease (CD), 7 with ulcerative colitis (UC) and 9 control subjects with grossly normal bowel. The percentages and absolute numbers of B cells and complement receptor-bearing lymphocytes in the patients with UC did not differ significantly from those of the control group; but in CD, the percentages of these cells were significantly decreased despite that the absolute numbers were normal. The percentages and absolute numbers of T cells identified by E rosettes (regular and stable) were normal in both CD and UC. In both diseases, significantly increased percentages but normal absolute numbers of mature T cells were identified by monoclonal antibody staining with the CD3 reagent. There was an increased proportion of suppressor/cytotoxic T cells and a concomitant significant decrease of the helper to suppressor T-cell ratio (using either percentages or absolute numbers of cells) in tissues from patients with CD, but not with UC as compared with the control group. These results suggest that the imbalance of T-cell subpopulations in the intestinal lamina propria may play a role in the pathogenesis of CD.

Mucin-like antigens in a human pancreatic cancer cell line identified by murine monoclonal antibodies SPan-1 and YPan-1.

The antigenic determinant recognized by monoclonal antibody SPan-1 is greatly elevated in sera of patients with pancreatic cancer but not in sera of normal individuals. Here we describe the mucin-like characteristics of the SPan-1 antigen isolated from culture medium and xenografts of the human pancreatic cancer cell line SW-1990. YPan-1, another pancreatic cancer associated monoclonal antibody, also reacts with the SPan-1 antigen. The SPan-1/YPan-1 antigens have densities of 1.4-1.5 g/ml and elute in the void volume of Sepharose CL-2B columns. They are resistant to degradation by chondroitinase ABC, nitrous acid, and hyaluronidase but susceptible to protease digestion and reductive beta-elimination. All these characteristics suggest that the SPan-1 and YPan-1 determinants are carried on mucinous antigens. Both SPan-1 and YPan-1 immunoreactivities are unaffected by boiling or by alkylation and reduction of the mucins while they are abolished by mild periodate oxidation or neuraminidase and are markedly decreased by wheat germ agglutinin. Thus, their antigenic determinants are composed principally of carbohydrates with sialic acid, an absolute requirement for reactivity. However, the epitope specificities of SPan-1 and YPan-1 are different since YPan-1 does not compete with SPan-1 for binding to antigen. Moreover, YPan-1 and SPan-1 can be distinguished from several other sialic acid requiring, cancer associated antibodies such as B72.3, CSLEX-1, DU-PAN-2, OC-125, and 19-9 by either their epitope characteristics or their tissue reactivity patterns.

Human pancreatic cancer-associated antigens detected by murine monoclonal antibodies.

Two monoclonal antibodies, YPan1 and YPan2, were produced from spleen cells of mice immunized against a human pancreatic cancer cell line, Capan-2, which also reacted with eight other human pancreatic carcinoma cell lines and with sections of cancerous human pancreas tissue. Reactivity was also found with colonic and stomach carcinoma tissues. Whereas YPan1 reacted strongly with normal pancreatic tissue, it bound weakly, if at all, to a variety of other normal tissues. YPan1 reacted with both the membranes and cytoplasm of pancreatic adenocarcinoma cells and with constituents of normal pancreatic ductal cells and duct luminal contents. YPan2, on the other hand, reacts to a greater degree with intracytoplasmic constituents in pancreatic adenocarcinoma cells. Unlike YPan1, YPan2 reacted weakly with only one of 16 cases of normal pancreas. Pretreatment of the tissue with neuraminidase abolished YPan1's reactivity, which indicated that sialic acid may be involved in the antigenic activity of the molecule(s) recognized by YPan1. Neuraminidase pretreatment had no effect on YPan2 reactivity. Neither YPan1 nor YPan2 competed with 19-9 monoclonal antibody in binding to soluble CA 19-9 antigen. These results suggest that these monoclonal antibodies are of potential use in the diagnosis of pancreatic carcinoma.

Circulating lymphocyte subpopulations in Crohn's disease.

Circulating lymphocytes were enumerated in 28 patients with Crohn's disease and in 12 patients with other diseases by rosetting and by immunofluorescent staining using monoclonal antibodies for T-cell surface phenotypic markers [OKT3 (mature), OKT4 (helper), and OKT8 (suppressor/cytotoxic)] or polyvalent antisera for surface immunoglobulins (B cells). Total lymphocyte counts were reduced only in those with non-steroid-treated active Crohn's disease. Circulating monocyte counts, proportions of peripheral T and B cells, and percentages and absolute numbers of mature, helper, and suppressor T-cell subclasses in Crohn's disease were not significantly different than in the controls. Helper to suppressor T-cell ratios were comparable in all subjects, varying directly with numbers of helper T cells (p less than 0.05). Individual ratios of helper to suppressor T cells did not correlate with disease activity or location, the use of steroids, serum albumin, or total lymphocyte or monocyte counts. This study provides no evidence for underlying abnormalities of circulating lymphocyte subpopulations in Crohn's disease when compared to subjects with other illnesses. The characterization of lymphocyte subclasses in affected tissues is an important area of continuing investigation.